We have recently showed a significant decrease in glutamate dehydrogenase activity (GDH) in leukocytes and fibroblasts of patients with olivoponto-cerebellar atrophy (OPCA). A number of studies are proposed by which we will attempt to find answers to the question whether this enzymatic defect is causally related to the clinical syndrome or is an associated epiphenomenon. We propose to: (1) Study the specificity of the defect for OPCA by measuring GDH in leukocytes of patients with various forms of spinocerebellar degeneration as well as other neurological disorders with system degeneration. (2) Investigate whether the enzymatic defect persists in cultured skin fibroblasts from these patients. (3) Explore whether the enzymatic deficiency follows the basic genetic defect in affected kindreds by measuring the enzyme in affected and unaffected (as well as obligated heterozygotes in recessive inheritance) family members. (4) Search for abnormalities of amino acid and ammonia metabolism in the blood and CSF of these patients by measuring the levels of these substrates. (5) Investigate for kinetic abnormalities of GDH as well as for possible alterations in its allosteric regulation in these patients. (6) Explore the possibility whether administration of L-leucine, an amino acid known to stimulate in vitro GDH, to patients with the enzymatic deficiency could have therapeutic effects. In addition, these studies may establish new criteria for biochemical classification of some degenerative neurological disorders.